The ability of subpopulations of murine spleen cells to stimulate a mixed lymphocyte response (MLR) was studied. It was found that T cells and B cells were poor stimulators of an MLR across H-2 or Mls differences. However, a non-T, radiation resistant splenic adherent cell (SAC) population was up to 20-50 times more efficient as a stimulator of these MLR's on a per cell basis than an unseparated spleen population. These SAC were shown to express Ia (I-region associated) determinants encoded by genes in I-A and I-E/C. These results suggest that Ia plus SAC may be the predominant stimulating cells in spleen cell populations, and the preferential target for T cell recognition in cell interaction events. It has further been investigated whether T cells responding to Mls determinants recognize such determinants in the context of "self" H-2 determinants. Studies employing limiting dilution techniques suggest that T cell responses to Mls involve the recognition of Mls in association with H-2.